Angiotensin converting enzyme (ACE) inhibitors are well established cardiovascular drugs used, in particular, for the treatment of hypertension and congestive heart failure.
(1S,9S)-9-[[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]octahydro-10-oxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (referred to herein as cilazapril) was first claimed in EP 0 094 095. In the same publication, cilazapril was identified as an Angiotensin Converting Enzyme (ACE) inhibitor useful in the treatment of hypertension. Cilazapril is the monoethyl ester prodrug of the corresponding dicarboxylic acid (cilazaprilate), which is the active form of the enzyme inhibitor. Cilazapril has been marketed since the early 1990's as cilazapril monohydrate by Roche under the name Dynorm® as a film coated tablet for oral administration.
A requirement in the treatment of hypertension is a sustained therapeutic drug level over a long period of time. This is not easily achieved with tablets, but can be obtained by topical delivery with a transdermal patch also commonly referred as therapeutic transdermal system (TTS). TTSs offer many other benefits in comparison with orally administered tablets, including avoidance of first pass metabolism (because the drug does not pass through the liver before reaching the systemic circulation); avoidance of gastro-intestinal side effects; the potential for zero-order drug delivery; reduced side effects (because of lower peak plasma concentrations); increased safety (by allowing the application of an accurately known dose to a clearly defined area); and improved patient compliance.
Unfortunately many orally administered drug candidates lack the necessary physicochemical properties that would allow them to permeate the skin to a clinically useful extent.
In U.S. Pat. No. 6,805,878 a transdermal therapeutic system of an ACE inhibitor such as enalapril is disclosed, wherein the flux of the drug present in the TTS is increased due to the presence of the more lipophilic derivative, enalapril ethyl ester.
In US 2009/0162420 the chemical stability problem of ACE-inhibitors in a semisolid dosage form, in particular due to the intramolecular lactam cyclisation leading to the formation of diketopiperazines, is addressed by the creation of salts of the ACE-inhibitor dicarboxylic acids with organic amines and/or with alkali compounds i.e. compounds containing an alkali metal cation.
Instability in a semisolid dosage form is also a problem with cilazapril. Although cilazapril has a more rigid structure than other ACE-inhibitors and has no distinct tendency to intramolecular cyclisation, it presents stability problems in adhesive layers of transdermal therapeutic systems as shown in Table 1.
TABLE 110% cilazapril in an acrylic adhesive (Durotak 87-4098, Henkel)Storage timeStorage conditionsassay [%]0 monthsuncontrolled98.13 weeks25° C./60% relative humidity98.07 months25° C./60% relative humidity91.93 weeks40° C./75% relative humidity95.97 months40° C./75% relative humidity80.4
US 2004/0052835 discloses that stabilization of ACE-inhibitors can be achieved in a TTS by diesterification of their metabolites, the ethyl ester of the ACE-inhibitors being preferred. However, it has been found that the ethyl ester of cilazapril is stable against enzymatic cleavage. Accordingly, although it is stable within the patch, the ethyl ester of cilazapril is not transformed in vivo into the pharmacologically active form of the ACE inhibitor and therefore is not suitable for transdermal dosage forms.
Moreover for transdermal therapeutic systems there exists a further requirement. The active ingredient, that is dissolved in the adhesive layer of the TTS, must stay in solution—i.e. crystals of the active ingredient must not form on the surface of the TTS. Accordingly crystallization in a transdermal therapeutic system is a further problem which has to be overcome.